The Science Of Anabolic

Steroid Abuse

Richard J. Auchus, MD, PhD

Division of Endocrinology & Metabolism
UT Southwestern Medical Center
Dallas, TX
 Androgens As Anabolic Agents
Myths

• Used Mostly By Professional Athletes

– ….Well, Maybe Intense Bodybuilders….
• Users Die of Cancer, Liver Failure, Strokes
– ….But Androgens Are Not Like Narcotics….
• It Is Not Germane To My Practice
• Have No Place In Good Medical Practice
 Androgens As Anabolic Agents
Reality

• Common In General Population

– Children To Businessmen; Entire Subculture
• Are Very Addicting In Specific Users
– Pose Other Risks To Users And Contacts
• You Will Encounter Users In Your Practice
• Will Play A Prominent Role In Medicine
– HIV, Cancer, Critical Illnesses, Elderly
 Anabolic Steroid Topics
• What Are They
• Who Uses Them, Why, and How
• Evidence of Efficacy/Mechanism of Action
• Types and Severity of Side Effects
• Detection Technologies
• Precursors and Their Metabolism
 Anabolic vs. Androgenic
• Anabolic: Ability to Aid Assimilation of
Nutrients (Nitrogen) Into Tissue
• Androgenic: Masculinizing Properties
• “Weak Androgens”= Precursors of Strong
– DHEA, Androstenedione
• Strong = Testosterone, Dihydrotestosterone
• Thus Far Inseparable
– Presumed Same Mechanism of Action
 Androgen Metabolism
17β-Dehydrogenation
(17β-HSD Type II)
OH
H
Aromatization
(Aromatase)

3α-Reduction
(3α-HSDs)

O
6α/6β-Hydroxylation
5α/5β-Reduction
(P450 3A4, etc.)
(5α/5β-Reductases)
 Testosterone & Derivatives
17β-Esterification
& 17α-Alkylation
OH

19-Nor

A-Ring
Modifications

O
5α-Reduction
 Target Organs and Physiological Effects
of Testosterone and Metabolites
• CNS (↑ libido, well-being, • Skin (↑ facial/ body hair,
aggression, spatial cognition) sebum production)
• Hypothalamus/ Pituitary • Bone (↑ BMD)
(↓ GnRH, LH, FSH; ↑ GH) • Muscle (↑ lean mass,
• Larynx (lowers voice) strength)
• Breast (E2 ↑ size) • Adipose Tissue (↑ lipo-
lysis, ↓ abdominal fat)
• Liver (↓ SHBG, HDL)
• Blood (↑ hematocrit)
• Kidney (↑ erythropoietin)
• Immune system (↓ auto-
• Genitals (↑ development, antibody production)
spermatogenesis, erections)
• Prostate (↑ size, secretions)
 Anabolic Steroid Abuse
Prevalence
• High School
– 3-12% M, 0-4% F; 30% Nonathletes
• College Athletes
– 2-30% M, 2-10% F
– Football, Track & Field
• Professional & Elite Athletes
– Estimated 30-100%
– Highest in Powerlifters, Bodybuilders
 Anabolic Steroid Users
Two Major Dichotomies
• Professional Athletes vs. Recreational
– Different Goals and Fear of Drug Testing
– Escalation Greater With Non-professionals
• Male vs. Female Athletes
– Men: All Sports, Greater in Power Sports
– Women: More Restricted Use
Bodybuilders, Track & Field, Sprint Swimmers
Usage Gaining In Other Sports & Youths
Steve Courson, Former Pittsburgh Steeler
Die Young
Die Strong
Dianabol ®
“I started in high school weighing
140 pounds; I was Mr. Nobody.
Sophomore year, I started
taking steroids--my weight
jumped 40 pounds and
everybody suddenly wanted to
be my friend. Since then I’ve
had girls on one side, guys on
the other. What more could I
want?”
 Anabolic Steroid Abuse
Getting Started
• Estimated 1,000,000 Users in USA
– Burgeoning Use of Androgen Precursors
• 50% Adolescent
• Peers, Coaches, Parents
• Sports Performance
• Social Acceptance
• Distorted Body Image
“I’m not sure if steroids will hurt
my body in the long run--it’s a
gamble--but I’m living in the
‘now.’ I keep striving to get
bigger--it’s like a disease. I’m 19
and weigh 200 pounds but still feel
too small.”
“Our role model is this older guy at
the gym....290 pounds without an
ounce of fat. That’s our goal.”
 Muscle Dysmorphia
aka Reverse Anorexia Nervosa
• Fear “Looking Small” Despite Being Muscular
• Want To Gain Weight But Be Lean, Muscular
• Avoid Body Exposure
• Exercise (Bodybuilding) Compulsively
• Obsessive Eating Behavior
• High Incidence Androgen Use
 Muscle Dysmorphia
Characteristics
M.D. Ctrl.
Number of Times You Weigh Yourself/Week 5.0 2.0
Number of Times You Check Mirrors/Day 9.2 3.4
Minutes/Day Preoccupied Being Small 325 41

Have You Worn Heavy Sweatshirts In

Summer Or Refused To Remove Shirt?
Yes 21 0
No 3 30
Have You Given Up Enjoyable Activities
To Go To The Gym To Get Bigger?
Yes 24 11
No 0 19
Olivardia et al Am J Psychiatry 157:1291-1296 (2000)
 Addiction
“You always end up taking
more than you planned.
Since it worked so good the
last time, you always want to
try more. I’m definitely
hooked.”
 Anabolic Steroid Addiction
• Psychological Dependency Common
– Feeling of Invincibility on Drugs
– Loss of Vigor and Size During Withdrawal
– Distorted “Too Small” Body Image
Perpetuates and Escalates Usage
• Physical Dependence Controversial
– Vasomotor Instability Responsive to Clonidine
 Anabolic Steroid Withdrawal
Biphasic Model
• First Phase (1-2 Weeks)
– Agitation, Vasomotor Instability
– May Require Hospitalization
– Rx: Sedatives, Clonidine
• Second Phase (Months)
– Depression, Lassitude
– Hypogonadal State Exacerbates Symptoms
– Rx: SSRIs, Testosterone Replacement
 Anabolic Steroid Abuse
Getting Someone Off
• Acknowledge Value of Fitness & Exercise
• Set Realistic Goals: Weight, Strength
• Psychological, Nutritional Counseling
• Importance of Good Sleep Hygiene
• Taper Androgens
– Set Schedule For Reaching Replacement Dose
– ??Benefit of β-hCG For Testicular Atrophy
 Anabolic Steroid Abuse
Sources
• Coaches, Sports Personnel
• Unscrupulous/Misguided Physicians
• Black Market, Mail Order, Internet
– ~$ 1 billion/year Plus OTC Precursors
– > 100,000 Suppliers
– 30% “Blanks”
• Veterinary Preparations
– Mibolerone, Boldenone, Injectable Stanozolol
 Anabolic Steroid Abuse
Patterns of Usage
• Cycles of 4-18 Weeks
• Drug Holidays of 1-12 Months
– Pre-competition Diuretic “Washout”
• Multiple Agents (“Stacking”)
• Tendency to Escalate Dose Each Cycle
• Drugs to Counteract Side Effects
 Anabolic Steroid Abuse
Polypharmacy To Negate Side Effects

Side Effect Agents

Gynecomastia Tamoxifen
Testolactone
Acne Tretinoin
Testicular Atrophy β-hCG

This Gets Pretty Expensive…

 Androgens: Do They Work??
Problems With Earlier Studies
• Largely Observational &Uncontrolled
• Selection Bias/Extrapolation of Results
• Blinding Impossible
• Informed Consent a Major Issue
• Duration of Studies
• Tendency to Increase Strength
– Continuously Training Subjects
– Methandrostenolone Rx, 1-RM Assessment
 Distance (meters)
19

Oral-Turinabol 18

Effect On Shot Put

Distance, GDR 17

Female Athlete 20

Distance (meters) 19

18

17
Supraphysiologic Testosterone
No Exercise + Exercise
Change Plac. Test. Plac. Test.
Weight (Kg) 1.3 3.5 0.9 6.0
Quads (mm2 ) 0 600 530 1,200
Bench (Kg) 0 9 10 22
Squat (Kg) 3 13 25 38

Bhasin et al NEJM 335:1-7 (1996)

 “Inside the Numbers”
Bhasin et al
No Exercise + Exercise
Placebo Test. Placebo Test.

∆Bench 0 2.2 8.4 2.8

∆ Wt
∆ Squat 1.8 2.9 18 4.7
∆ Wt
 Conclusions & Limitations
Bhasin et al
• Supraphysiologic Testosterone Doses
(600 mg/wk) Increases FFBM, Strength
• Weight Gain Predominates
• “No” Change in Mood, Behavior --BUT
• 10 Week Study; No Post-Rx Follow-up
• Cannot Extrapolate to Elderly or Ill
• Cannot Extrapolate to Other Regimens
Supraphysiologic Testosterone
Effects On Mood & Aggression
Placebo Testosterone
Start End Start End
YMRS 0.3 1.1 0.5 3.9**
*p<0.05
PSAP 208 222 208 362* **p<0.01
Manic 7.9 7.4 7.5 9.2**
Score
Liking 50 50 51 55**
Score
Pope et al Arch Gen Psychiatry 57:133-140 (2000)
 “Inside the Numbers”
Pope et al
• Three Groups Of “Responses” To Testosterone
– Marked (YRMS >20, Likely Manic Impairment): 2
– Moderate (YRMS 10-19, Milder Hypomanic): 6
– Minimal (YRMS<10): 42
• Placebo Period: 1 Moderate
• Conclusions—Supraphysiologic Testosterone:
– ~5% Of Males Manic/Hypomanic; ~10% Partial
– Lower Limit Of True Incidence (Dose, Duration)
– Variable Responses Amongst Individuals
Marked Response
Manic
Response To
Testosterone
Moderate Response Pope et al

No Response
 Anabolic Action of Androgens
Mechanistic Conundrums
• Cannot Extrapolate Data From Sexually
Dimorphic Muscles in Lower Species
• Difficult to Demonstrate AR Protein,
mRNA in Human Skeletal Muscle
• Classical Paradigm Fails to Explain Need
for Supraphysiologic Concentrations
• Molecular Techniques Have Not Identified
Target Genes (?IGF-1, Myostatin)
Anabolic Action of Androgens
Theoretical Dose-Response Curves

Supraphysiologic
Muscle Mass

Eugonadal

Hypogonadal

Androgen Dose
 Model For Androgen Action
Anabolic Steroid Excess

More ??Direct
Maintains Blocks
Aggressive Action On
Eugonadism Catabolism
Training Muscle

Adequate Strength & Continued

Diet Performance Training
Gains
 Anabolic Steroid Abuse
Side Effects: CV, Liver
• Cardiovascular
– Cardiomyopathy, HTN, Strokes, MIs
• Liver: Primarily Oral Agents
– Hepatocellular Damage, Cholestasis
– Peliosis Hepaticus, Tumors, CA
• Dyslipidemia
– Raises LDL-C (Orals), Lowers HDL-C (All)
– Activation of Hepatic Lipase
 Anabolic Steroid Abuse
Side Effects: Brain
• Euphoria, Hypomania, Delusions, Paranoia
• Aggression, Rage, Murders, Sexual Abuse
– Aggression “Beneficial” to Some Athletes
– Gender Preference Same, Libido Increased
• Depression, Suicides During Withdrawal
• “Roided Out” Syndrome
– Catastrophic Demise
 Anabolic Steroid Abuse
Side Effects
• Children
– Epiphyseal Plate Fusion
– Disrupt or Initiate Puberty
• Infections
– Abcess/Cellulitis in “Spot Shots”, HIV, Hepatitis
• Tendon Ruptures (? Overtraining)
• Acne, Pattern Baldness, Striae, Edema
• Polycythemia
 Anabolic Steroid Abuse
Side Effects: Male
• Infertility
– Incidence Increases With Duration of Use
– Can Reverse With Discontinuation & β-hCG
• Gynecomastia
– Aromatizable Testosterone Esters
• Prostatic Hyperplasia, ?CA
 Anabolic Steroid Abuse
Side Effects: Female
• Amenorrhea
• Breast Atrophy
• Hirsutism
• Clitoromegaly
• Deepening of Voice
• Often Prominent and Irreversible
“Many of the athletes you now see
pictured in this magazine will be
dead within 10-15 years. Their
deaths will not be painless. The
abusive use of anabolic steroids
will make their passing an ugly
sight, as cancer rips through
their bodies, unmercifully eating
them up alive.”
-Bob Goldman
‘Death in the Locker Room’
“To say that steroids are dangerous is like
saying that skydiving is dangerous, or
skate boarding, or your bath tub…..
We have also not told you any horror
stories of steroid abuse because we
really don’t know any. We personally
have not encountered athletes dying or
becoming gravely ill from steroid usage.
Sick people, we have, but not healthy
athletes.”
-Underground Steroid Handbook, 1st Ed.
“I get side effects, like bloating,
acne and a sore chest and
nipples. But I don’t mind. It
lets me know the stuff is
working. Most guys say, ‘Cool,
it’s real juice’.”
-Teenage User
 Drug Testing Technology
• Synthetic Steroids: GC/MS of Metabolites
– HPLC-MS of Conjugated Metabolites
• Testosterone: T/Epi-T Ratio > 6 (nl < 2)
– T/LH > 30; Ketoconazole Suppression Test
• Ratios of 5α:non-5α C19 Steroids
• Isotope Ratio Mass Spectrometry
 Urine Sample
C-18 or XAD
Solid Phase Extraction
Enriched Pool of Steroids,
Glucuronide and Sulfate Conjugates
β-Glucuronidase
Hydrolysis

Steroids & Steroid Sulfates

Organic Solvent
Extraction

Steroids
MSTFA Derivitization
+ Enol Catalyst

Steroid TMS-(enol)-
Ether Derivatives
19-Norandrosterone

m/z abundance
169.10 35%
225.20 18%
315.30 26%
405.30 100%
420.30 80%
 Detecting Dihydrotestosterone
• Problems: Short t1/2, Endogenous DHT
• Isotope Ratio Mass Spectrometry
– 13C Content of Endogenous vs Exogenous DHT
– δ13C%% < -29 Suggests Exogenous Source
• Ratios of 5α:non-5α C19 Steroids
– 5α-/5β- Androsterone-3α,17β-diols
– Developed by Mitsubishi Chemical Co.
– Busted Chinese Swim Team ‘94 Asian Games
 DHT: Chinese Women Swimmers
Athlete DHTcorr 5α/5β-Α 5αA/Etio DHT/EpiT
1 388.67 56.61 5.70 83.14
2 89.54 12.65 1.99 24.77
2 60.73 10.21 1.92 13.22
2 77.40 10.62 1.99 29.07
2 47.93 17.75 2.26 17.43
3 18.63 14.02 2.53 4.73
4 16.38 67.88 2.91 9.38
5 28.70 62.45 2.52 6.42
5 15.68 70.52 2.51 7.80

Upper Limit: 12.13 1.88 2.20 2.72

 Diosgenin
CH3
Stigmasterol
O
H3C CH3 CH3

H3C H3C
O
H3C CH3

HO CH3 CH3
HO
δ13C Values For High T/EpiT Ratio

Athlete T/Epi-T 5βΑ 5αΑ 5βP 5βP-5βΑ 5βP-5αΑ

1 40 -30.42 -31.96 -25.67 4.8 6.3
2 29 -31.43 -34.57 -26.14 5.3 8.4
3 80 -28.76 -31.25 -23.06 5.7 8.2

4 10 -25.32 -25.76 -24.54 0.8 1.2

5 9 -24.82 -25.47 -23.49 1.3 2.0
6 8 -24.62 -26.04 -23.36 1.3 2.7

Control -25.69 -26.35 -24.26 1.43 2.09

SD 0.92 0.68 0.70 0.68 0.63
 Drug Testing
Strategies to Avoid Getting Caught
• Use Agents That Are Difficult to Detect
• Abstention Peroids
– Synthetic Injectables Can Last > 6 Months
• Diuretics to Dilute Urine
• Bacterial Contamination
• Tampering With Samples
 Recent Developments
The Good News
• DEA: Androgens Labeled CIII Drugs
• Ciba: Discontinued Dianabol Production
• Transdermal Testosterone Preparations
• Medical Community Recognition
– Scope of Problem and Motivation of Users
– Interest In Studying Issue Scientifically
• Sports: Random Testing, Better Methods
– Decline In Women’s Strength Events
 Recent Developments
The Bad News
• Evidence of Increased Use in Females
• Professional Strategies To Subvert Testing
– Shift To T, DHT & Derivatives
– Boutique Labs Synthesize Custom Androgens
– Usage Infiltrating All Sports
• Precursors as “Nutritional Supplements”
 Dietary Supplements Health and
Education Act of 1994 (DSHEA)
• “Dietary Supplements” Exempt From
Premarket Safety Evaluations
• Defined As Any Product Containing a “Dietary
Substance” Labeled As “Dietary Supplement”
• Adulteration With Untested Ingredients Allowed
If Inadequate Data To Exclude Risk
• Truth, Safety Is Manufacturer’s Responsibility
 DHSEA: The Bottom Line
• You Can Sell Practically Anything You Want As
A “Dietary Supplement”
• You Do Not Need To Prove That It Is Safe Before
You Start Selling It
• You Can Interpret Any Data However You Want
To Claim Benefit For “Structure or Function”
• The Onus Is On The FDA To Prove Guilt/Harm
– The FDA Has Never Successfully Prosecuted a Case
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4 Androstendiol ------------ 75 mg
5 Androstendiol ------------ 75 mg
4 Androstene 3, 17 Dione --- 75 mg
Tribulus Terrestis --------- 500 mg
Chrysin -------------------- 100 mg
Phosphatidyl Serine -------- 200 mg
Saw Palmetto --------------- 250 mg
Zinc (Glycinate) ----------- 8 mg
 Androstenedione
-One Step From Testosterone
17β-HSD III & V O
-Preferred Aromatase Substrate

O
 Cholesterol Androgen Biosynthesis:
StAR
PBR
P450scc/Adx/AdR Traditional Pathways
Pregnenolone
CYP17 17α-hydroxylase
CPR (b5) 17, 20-lyase
3βHSD I & II aromatase
DHEA Androstenedione Estrone
CPR

17βHSDII
17βHSDIII

17βHSDI
17βHSDII
17βHSDV

aromatase
Testosterone Estradiol
CPR
5α-Reductase I & II
3αHSD
Dihydrotestosterone Androstanediol
 Androstenedione
• Sparse Data About Oral Use Before 1998
• Robust Metabolism By Hepatic P450s
• Banned By Most Sports Authorities
• Safe?? Efficacy?? Placebo??
• Dietary Supplement????
 Oral Androstenedione
Strength, Testosterone, Estrogens
• Circulating Testosterone Concentrations
– No Effect At 100 mg/d (King)
– Variable Small Rise At 300 mg/d (Brown, Leder)
• Strength: No Effect Shown (King, Broeder)
• Estrogens: Consistent, Marked Elevations

King et al JAMA 281:2020-2028 (1999)

Brown et al Int J Sport Nutr Exerc Metab 10:340-59 (2000)
Leder et al JAMA 283: 779-782 (2000)
Broeder et al Arch Intern Med 160:3093-3104 (2000)
 DHEA
-19-Carbon (Androstane) H3C
O
-∆5, 3β-Hydroxy, 17-Keto
-SO4, Ester At 3β H3C

HO
 DHEA: How Does It Work?
• Conversion To Androgens
– 50 mg/d Raises Testosterone In Women
• Intrinsic Activity Of DHEA(S) In Brain
– Trophic Effects On Cultured Neurons
– GABA, NMDA, Sigma Receptor-Channels
• Actions Of Weird Metabolites:
The “Neurosteroids” Concept
Neurosteroids & 3α,5α-Pathways
Precursors
CYP17 5α-Red-I
•Pregnenolone
17βHSDIII 3αHSDs
•Progesterone
5α-Red-II CYP17/SLTase

Androgens Neurosteroids
•Testosterone HO •Allopregnanolone
H
•Dihydrotestosterone •Dihydroprogesterone
•Preg(-S), DHEA-(S)

Nuclear Hormone Receptor Ion Channels

Genomic Actions Non-Genomic Actions
Steroid Hormone Action: Dichotomy?
 Allopregnanolone
Potentiation of GABA/Cl- Currents
 Synthetic Androgens
Potentiation of GABA/Cl- Currents
 Neurosteroids & Androgens
Precursors
CYP17 5α-Red-I
•Pregnenolone
17βHSDIII 3αHSDs
•Progesterone
5α-Red-II CYP17/SLTase

Androgens CYP17 Neurosteroids

•Testosterone 17βHSDIII •Allopregnanolone
•Dihydrotestosterone 3αHSD •Dihydroprogesterone
•Preg(-S), DHEA-(S)

Nuclear Hormone Receptor Ion Channels

Genomic Actions Non-Genomic Actions
 Anabolic Steroid Abuse
Conclusions
• Prevalence High
– Athletes, Adolescents, Increasing in Girls
• Psyche Predisposes to Escalating Use
• Aids in Weight > Strength, Not Endurance
• Mechanism Complex
• Side Effects Numerous Albeit Mostly Rare
• Precursor Use Out of Control
• Sparse Data, Careful Studies Needed
“We’re not freaks or
addicts. We’re using
modern science to reach
our goals.”